(117h) Regularizing Binding Energies and the Thermodynamics of Hydration --- an Approach to Study the Hydration Free Energy of a Protein From All-Atom Simulations

The interaction of a hydrated solute with the solvent spans a wide range of energies. Interactions with the solvent adjacent to the solute are typically strong (relative to thermal energy), and, in the case of ionic solutes, the strength of these interactions can rival covalent bonds. Farther away from the solute-solvent interface, the interaction weakens and the distribution of interaction energies approaches a Gaussian. Traditionally, in computing the thermodynamic properties of hydration, the problem of disparate energy scales is dealt by alchemically transforming the solute from a non-interacting solute to a fully interacting solute. But at the scale of a globular protein such approaches can prove challenging. Here, guided by the quasichemical organization of the potential distribution theorem, we present an approach that readily applies to systems ranging in complexity from those described by first principles (ab initio) potentials, a challenge that has thus far remained formidable, and to study the hydration thermodynamics of a protein, potentially at a level of resolution that is now routine for small solutes in water. The latter possibility can help address fundamental questions regarding the thermodynamics that govern the structure and stability of proteins. In this presentation, we will show results of our approach for the hydration of water, of a peptide model in different osmolyte mixtures, and finally for the protein cytochrome C. The potential utility of this approach for studying ion and osmolyte-specific effects in protein solution thermodynamics will be indicated.